The induction of neutralizing immunity to Plasmodium falciparum toxins by vaccination has been proposed as a preventive strategy to limit the severity of malaria. For this approach to be successful, generation of a sustained immune response would be necessary. This study shows that immunoglobulin G (IgG)-subclass responses elicited by the proposed P. falciparum toxin glycosylphosphatidylinositol (GPI) in Papua New Guinean subjects 5-60 years old predominantly involve IgG3, with a lesser contribution from IgG1 and an absence of IgG2 and IgG4. IgG3 levels declined sharply within 6 weeks of pharmacological clearance of parasitemia in all subjects, whereas a significant decrease in IgG1 levels was seen only in subjects ≤19 years old. Because the natural antibody response to P. falciparum GPIs is skewed toward the short-lived IgG3 subclass, a vaccination strategy with GPI analogues would likely require augmentation by costimulatory molecules, to induce a more persistent anti-GPI response.